OCD is a severe, heritable condition with a lifetime prevalence of about two percent of world populations. The mode of inheritance is not well understood but is likely complex, involving multiple loci of small to moderate effect. Our laboratory has been active in studies of OCD and of its genetics for over 15 years, and was one of the founding sites of a multi-center genome-wide study of OCD, In addition, a series of association studies of candidate genes is continuing.[unreadable] Initial analysis revealed suggestive linkage signals on chromosomes 3q27-28 (P=0.0003), 6q (P=0.003), 7p (P=0.001), 1q (P=0.003), and 15q (P=0.006). Using the 'broad' OCD definition, the strongest evidence for linkage was found on chromosome 3q27-28. The collaborative group is currently pursuing fine mapping in these five regions. Given probable etiologic heterogeneity in OCD, mapping genes involved in the disorder may be enhanced by replication studies, large-scale family-based linkage studies, and the application of novel statistical methods. An example is a new finding that concentrating on one phenotype within OCD, i.e., hoarding behaviors, a distinctly different, highly significant intense signal was observed on 14p (LOD = 3.7).[unreadable] In addition, within the NIMH-IRP, exploratory analyses of DNA, clinical phenotypes and other features of >300 OCD probands plus 700 of their relatives with or without OCD-related disorders are being used to assess the candidacy status of gene variants and to better define a familial OCD phenotype. In one such study, factor and cluster analysis of 70 OCD symptoms in the probands revealed a four-factor grouping of symptoms, which showed specific relationships to comorbid psychiatric disorders. In a gene-based follow-up to this study, an association was replicated between the SLC6A4 5HTTLPR functional polymorphism and the symmetry/counting/ordering (Factor II) dimension of OCD symptoms. In further studies of the SLC6A4 gene in OCD and related disorders such as Tourettes syndrome, the 5HTTLPR together with two newly discovered SNPs (rs25531, rs25532) within it were found to be associated with OCD in both a case-control and a family-based trios study. Neuropsychiatric disorders are not thought to be the result of any one gene but most likely reflect a genetically complex configuration of multiple genes in multiple systems interacting together and in the environment. Their exploration seems to be a necessary next step in considering serotonergic, glutaminergic and other genetic involvement in these and related disorders. [unreadable] Many of the phenotypes discovered in SERT-targeted mouse models (Murphy and Lesch, 2008) have been glimpsed in studies examining the association of human diseases or traits with common human SLC6A4 variants, as well as the less common I425V, I425L, and G56A variants in SLC6A4 coding regions. Humans with the 5HTTLPR SS genotype closely resemble heterozygote slc6a4 +/- mice in regard to levels of SERT expression and function. These similarities allow predictive appraisals of phenotypes across species. Thus, it is no surprise to find that anxiety and depression-related personality traits and affective disorders plus alcohol and other drug dependencies, as well as some sleep and thermoregulatory disorders and the serotonin syndrome are associated with SLC6A4 variants in humans and other species, especially when interactions between SLC6A4 and life stress are taken into account. [unreadable] One example of a rare variant associated with OCD is SLC6A4 Ileu425Val, a missense SNP producing a gain-of-function and loss of normal regulation of the serotonin transporter. This was found to segregate with a primarily obsessive-compulsive disorder but complexly-comorbid phenotype in two studies evaluated in 2008 that showed SLC6A4 I425V as having a 1.5% prevalence in 530 individuals with OCD from five unrelated families and a 0.23% frequency in four control populations totaling 1300 individuals, yielding a significant OCD-control difference (Fisher's exact test corrected for family coefficient of identity p = 0.004, odds ratio = 6.54). SLC6A4 I425V was the first SERT coding region variant demonstrated to be functional and proposed to be associated with an OCD spectrum phenotype. SLC6A4 I425V has been designated OCD1 in Online Mendelian Inheritance in Man (OMIM). It is located in transmembrane domain 8 of the transporter, where it may modify the -helical secondary structure of the SERT protein and thereby transport function or where it may more directly affect the 5-HT translocation channel. Expression studies of SLC6A4 I425V cDNA in COS7 and HeLa cells documented a transporter gain-of-function via constitutive activation of serotonin transport in a nitric oxide-dependent pathway that resulted in an approximate two-fold increase in serotonin uptake accompanied by an increase in serotonin affinity. The high resolution structure of a bacterial SERT homologue shows that transmembrane domain 8 contributes to the substrate binding site and that the position corresponding to SLC6A4 I425 interacts with residues (Ser-190 and Leu-191) in transmembrane domain 3, which also contribute to the binding site. This may be responsible for the recently reported differential ability of SRIs to interact with SERT function: SLC6A4 I425V was associated with decreased potency of sertraline and citalopram to inhibit serotonin transport; furthermore, sertralines potency to inhibit binding of 125I--CIT was reduced by SLC6A4 I425V in transfected HeLa cell lines.[unreadable] SLC6A4 I425V and other rare gene variants associated with OCD phenotypes are represented in less than 2% of OCD cases. Investigation of rare candidate genes and chromosomal regions is an alternative to the broader scale genome-wide evaluations of the dominant hypothesis of common variants accounting for common diseases. It seems possible that a relatively common disease like OCD might well have uncommon, more highly penetrant functional variants that might more directly contribute to the common OCD phenotype. [unreadable] When the entire 5HTTLPR was sequenced to identify for additional common and possibly functional variants, our group observed that a common SNP, rs25532, strongly modulates 5HTTLPR-conferred SERT expression. When 5HTTLPR and other SLC6A4 SNPs were included in a haplotype analyses, our group discovered a highly significant omnibus association in this large 2008 case-control sample. Remarkably, and in keeping with the hypothesis of increased SERT functioning in OCD, a haplotype containing the higher-expressing variant at each locus was significantly more common in OCD probands than in controls. The phenotypic abnormalities associated with human SLC6A4 have been partially anticipated from prior knowledge of the multiple roles for serotonin found in earlier physiologic and pharmacologic studies, but the extent of these associations now documented in over four hundred papers (mostly investigating our originally-reported 5HTTLPR polymorphism was unanticipated. The strong relationship of this polymorphism to treatment responses to serotonin reuptake inhibitors in humans and the related susceptibility of Slc6a4-deficient mice to fail to respond to SRIs and to develop serotonin syndrome abnormal behaviors represent additional new illustrations of gene-based influences on serotonergic pharmacologic responses a new SERT pharmacogenomics.